Ulipristal Acetate (UPA, previously named CDB-2914, a progesterone receptor modulator developed by the National Institutes of Child Health and Human Development (NICHD)), has potential use in contraception, treatment of fibroids and other gynecological indications [1]. UPA binds strongly to the progesterone receptor (PR), and delays ovulation in fertile women. It has been recently approved by the FDA and the European Medicine Agency as a single oral dose for emergency contraception [2]. In the previous grant period, we proposed the development of a novel estrogen-free, bleed-free long-term contraceptive method employing a UPA contraceptive vaginal ring (CVR) which would deliver the PRM continuously for a 3-month period. We identified the effective dose to suppress ovulation first in animal models in preclinical studies and then in women. The results justify further development. In the current cycle, we propose to study the endometrial safety and contraceptive efficacy of a sequential regimen consisting of a UPA vaginal ring (UPA CVR) in combination with a single oral dose of progestin treatment every month. A reformulated 3-month vaginal ring with an innovative design will be tested for a 6-month study. We will also pursue the development of an intrauterine system (IUS) delivering low daily doses of UPA to decrease endometrial thickness and bleeding, without blocking ovulation. It is anticipated that this novel approach may lead to a long-acting contraceptive with no monthly bleed while ovulation is maintained. Molecular mechanisms underlying potential health benefits of the UPA CVR on target tissues will be evaluated using novel techniques with the objective to demonstrate the potential protective effects benefiting breast health and assuring safety for endometrial tissue. Key novel target genes of interest have been identified as potential mediators underlying the proposed breast protection and health benefits of the UPA CVR. We will focus on detailed analyses of these genes and their downstream molecular signaling pathways in the proposed funding cycle. A new multiplex flow cytometry screening tool is under development for use in contraceptive R&D. It is anticipated that new targets for next generation contraceptives will be identified.